The purpose of this project is to study mechanisms of formation of supersaturated gallbladder bile and to develop mechanisms for its prevention. This past year we have studied factors regulating the secretion of different biliary lipids in bile. We have shown that the degree of coupling of cholesterol and phospholipids at low secretion of bile acids is a major determinant of supersaturated (lithogenic) bile. The degree of coupling was found to be variable from person to person which might explain differences in susceptability for gallstone formation. One of the factors leading to supersaturated bile in the fasting state at low bile acid secretion is the degree of obesity. We have continued our studies on the relation between obesity and lithogenic bile. Specifically, we have shown that it is not possible to desaturate bile with chenodeoxycholic acid (CDCA) in obese subjects during maintenance of weight. On the other hand, CDCA therapy is effective in decreasing lithogenicity of bile during caloric restriction, and thus it may be possible to decrease the danger of gallstones in obese persons undergoing weight reduction by taking CDCA. Our plan for next year is to continue to investigate the factors that regulate the saturation of bile in obese subjects with special emphasis on the fasting state when bile is entering the gallbladder. In particular we will determine the relative influence of cholic acid and CDCA on cholesterol-phospholipid dissociation in bile and on cholesterol absorption; the latter too may be another factor that influences bile lithogenicity.